Annexin 1: a new paracrine agent secreted by a novel mechanism

Glucocorticoid feedback on the pituitary inhibits the secretion of many pituitary hormones, including ACTH, growth hormone and prolactin. This inhibition involves not only the relatively slow genomic inhibition of hormone synthesis via classical intracellular glucocorticoid receptors but also much a more rapid inhibition which is independent of transcription. Annexin 1 is a protein produced by the folliculo‐stellate cells of the pituitary. Antibodies and antisense to annexin 1 block this more rapid inhibition. We now show that, despite the fact that annexin 1 lacks a signal sequence and is not packaged in secretory granules, glucocorticoids cause the externalisation of annexin 1 to a membrane‐associated pool (calcium‐dependent and bound to phospholipid) from which annexin 1 can be released. Annexin 1 is externalised at specific points on the membrane of a folliculo‐stellate cell line; these may correspond to the points at which folliculo‐stellate cells are attached to endocrine cells in situ. The externalisation of annexin 1 can be blocked by the sulphonylurea glyburide, an inhibitor of ATP‐binding cassette (ABC) transporters which can translocate other large proteins across membranes. ABC1 transporter protein and mRNA are both present in pituitary folliculo‐stellate cells. Annexin 1 is not restricted to the pituitary, but is widely distributed in macrophages and other tissues in which it is involved in the suppression of inflammation. It therefore appears that paracrine regulation can be exerted by a protein that is not packed in secretory vesicles and which is externalised from cells by a mechanism very different to that which controls the secretion of most peptides and proteins.